Malaria is the world's most widespread infectious disease. More than 300 million people are infected, and about 2 million die of it each year..sup.1 Curing malaria by treatment with alkaloids like quinine and chloroquine is becoming less effective due to the continuous emergence of malaria parasites resistant to these drugs.
A new approach to malaria chemotherapy, which is raising high expectations, is based on the use of cyclic peroxides..sup.2 Indeed, artemisinin, an endoperoxide sesquiterpene, was introduced in China as a drug in 1987..sup.3 In Western countries several compounds structurally related to artemisinin were clinically tested, but due to pharmacokinetic drawbacks and incomplete toxicological profiles, none of them were approved as a drug. Cyclic peroxide yingzhaosu A was isolated from a Chinese folk medicine, but no significant physiological and pharmacological data have so far been reported..sup.4
Recently, scientists at Hoffmann-La Roche reported on the synthesis, antimalarial screening and clinical trials of 7-oxo-2,3-dioxabicyclo[3.3.1]nonanes, bearing at C(4) alkyl- or alkenyl substituents..sup.5-7 In vitro and in vivo antimalarial screening, as well as clinical trials of arteflene, the most active compound in this series, gave encouraging results. ##STR1##
Biological evaluation of a variety of cyclic peroxides indicates that a number of them are effective non-toxic antiparasitic agents. However, parasitic infections, particularly malaria, remain a serious and widespread public health problem, and concern exists about possible side-effects of compounds developed to date. For example, neurotoxicity has been seen in rats which were administered high doses of artemether, and in mouse neuroblastoma cells treated with dihydroarte-mesinin..sup.8
It would be highly desirable to develop improved therapeutic agents for prevention and treatment of malaria.